CN103755686B - The piperidyl with platelet aggregation inhibitory activity replaces 5-hydroxyryptophan derivative - Google Patents
The piperidyl with platelet aggregation inhibitory activity replaces 5-hydroxyryptophan derivative Download PDFInfo
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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Abstract
The present invention relates to pharmaceutical chemistry field, be specifically related to a kind of piperidyl with platelet aggregation inhibitory activity and replace 5-hydroxyryptophan derivative (I) and preparation method thereof and application pharmaceutically, wherein R1、R2The same description of definition with n. Pharmacodynamics test proves, piperidyl of the present invention replaces 5-hydroxyryptophan derivative and has good platelet aggregation inhibitory activity.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to a kind of 5 preparations of tryptophan derivative that have piperidines to replaceMethod and application pharmaceutically.
Background technology
Along with China's population aging degree is increasingly sharpened, the incidence of thrombotic diseases constantly rises, and it is a kind of normalThe cardiovascular and cerebrovascular diseases of seeing, often show as myocardial infarction, Ischemic Cerebral Infarction, VTE etc. The whole world is died from such every yearThe number of disease approaches 1/4 of the total death toll in the world, becomes the No.1 killer of serious harm human health and life security.
Integrin is one of important glycoprotein receptor family of surface of cell membrane, its function be mainly mediation various kinds of cell itBetween and adhesion between cell and extracellular matrix. Wherein, integrin alpha IIb β 3 (is called again human platelet glycoprotein memebrane protein GPIIb/IIIa) be the platelet membrane acceptor that platelet surface content is maximum. The part of its identification mainly comprises fibronectin (FN), fibrinogen (Fg) and false vWF ELISA (vWF). Under blood platelet quiescent condition, GPIIb/IIIa'sAffinity is lower, in the time being subject to the stimulation of physiological derivant, and platelet activation, the GPIIb/IIIa acceptor of part and activationSpecific binding forms the final shared pathway of platelet aggregation. Therefore, blocking-up GPIIb/IIIa acceptor and fibrinogenicIn conjunction with affecting hematoblastic gathering, be at present the most efficiently, the method for the strongest platelet aggregation-against, in thrombosis, playImportant function.
Theoretically, the more traditional antiplatelet drug of GPIIb/IIIa receptor antagonist effect (aspirin, clopidogrelDeng) more comprehensively, thoroughly, effectively, therefore, powerful anti-platelet agent-platelet membrane glycoprotein GPIIb/ of a new generation in recent yearsIIIa receptor antagonist receives people's concern day by day. The research of GPIIb/IIIa receptor antagonist class medicine has very importantMeaning.
Summary of the invention
The invention discloses the 5-hydroxyryptophan that piperidyl that a class has good platelet aggregation inhibitory activity replaces derivativeThing (I), is specifically related to a kind of 5 tryptophan derivatives that have piperidines to replace. Structural formula is as follows:
Wherein R1Represent H, CH3Or CH2CH3；
R2RepresentWherein R3Represent the C replacing arbitrarily1-C10Alkyl, any C that replaces1-C10Alkoxyl,The phenyl replacing arbitrarily, benzyl, the C of replacement arbitrarily1-C10Carboxyl or 4-7 unit fragrant heterocycle, wherein alkyl or the alkane replacing arbitrarilyThe substituting group of oxygen base is hydrogen, halogen, hydroxyl, cyano group or amino; The substituting group of phenyl, benzyl or fragrant heterocycle is hydrogen, halogen, nitreBase, amino, hydroxyl or C1-C10Alkoxyl;
R2Also representWherein n1Or n2=0-10, R4 represents halogen, hydroxyl, cyano group, ammoniaBase, any C replacing1-C10Alkyl or the C replacing arbitrarily1-C10Alkoxyl, wherein substituting group is hydrogen, halogen, hydroxyl, cyanogenBase or amino;
R2Also representR5Represent the C replacing arbitrarily1-C10Alkyl, any C that replaces1-C10Alkoxyl, appointThe phenyl that meaning replaces, any benzyl replacing, wherein the substituting group of alkyl and alkoxyl is hydrogen, halogen, hydroxyl, cyano group or ammoniaBase; The substituting group of phenyl or benzyl is hydrogen, halogen, nitro, amino, hydroxyl or C1-C10Alkoxyl;
n=0～5。
Wherein R2Preferably represent bytyry, fourth sulfonyl, benzoyl, pyridine-4-carbonyl or 2-carboxyl acetyl group.
The preferred part of compounds of the present invention is as follows:
Compound 1:2-acetyl-amino-3-[5-(piperidin-4-yl Oxy-1 H-indol-3-yl]-propionic acid
Compound 2:2-propiono amino-3-[5-(piperidin-4-yl Oxy-1 H-indol-3-yl]-propionic acid
Compound 3:2-bytyry amino-3-[5-(piperidin-4-yl Oxy-1 H-indol-3-yl]-propionic acid
Compound 4:2-benzoyl-3-[5-(piperidin-4-yl Oxy-1 H-indol-3-yl]-propionic acid
Compound 5:2-(methyl isophthalic acid-sulfonamido-3-[5-piperidin-4-yl Oxy-1 H-indol-3-yl]-propionic acid
Compound 6:2-(butyl-1-sulfonylamino-3-[5-piperidin-4-yl Oxy-1 H-indol-3-yl]-propionic acid
Compound 7:2-bytyry amino-3-[5-(piperidin-4-yl methoxyl group-1H-indol-3-yl]-propionic acid
Compound 8:2-benzoyl-3-[5-(piperidin-4-yl methoxyl group-1H-indol-3-yl]-propionic acid
Compound 9:3-[5-(piperidin-4-yl methoxyl group-1H-indol-3-yl]-2-[(pyridine-4-carbonyl)-amino]-thirdAcid
Compound 10:2-(butyl-1-sulfonylamino-3-[5-piperidin-4-yl methoxyl group-1H-indol-3-yl]-propionic acid
Compound 11:2-(2-carboxyl acetyl-amino-3-[5-(piperidin-4-yl methoxyl group-1H-indol-3-yl]-propionic acid
Compound 12:2-bytyry amino-3-[5-(piperidin-4-yl ethyoxyl-1H-indol-3-yl]-propionic acid
Compound 13:2-benzoyl-3-[5-(piperidin-4-yl ethyoxyl-1H-indol-3-yl]-propionic acid
Compound 14:2-(butyl-1-sulfonylamino-3-[5-piperidin-4-yl ethyoxyl-1H-indol-3-yl]-propionic acid
In the present invention, compound and the pharmaceutically acceptable salt thereof with general formula (I) can be used for preparing human platelet glycoprotein filmThe purposes of the medicine of Protein G PIIb/IIIa acceptor inhibitor and treatment thrombus disease.
The compounds of this invention can be with pharmaceutically acceptable salt in conjunction with salify. Pharmaceutically acceptable salt can be with havingMachine or inorganic base form. For example, with alkali metal or alkaline-earth metal (as sodium, potassium, calcium or magnesium) or organic base and N-tetraalkylammonium salt(as N-4-butyl ammonium) salify. Can be by organic or inorganic acid salify for formula (I) compound with basic group. ExampleAs can with hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, lactic acid, citric acid, tartaric acid, butanedioic acid, fumaric acid, MalaysiaAcid, tussol, malic acid, camphoric acid and similar known acceptable acid salify.
The compounds of this invention also can adopt makes ester, carbamate and other prodrug forms, when giving with this formWhen medicine, it changes activity form onset in vivo into.
Compound of the present invention can be with following method preparation, with R1Expression hydrogen is example, and method comprises:
In the compounds of this invention general formula (I), in the time of n=0 or 1, its preparation process is as follows:
This series compound is preparation method comprise: 5-hydroxyryptophan is by being hydrolyzed under esterification, introducing acyl group, alkali conditionObtain replacement-5-hydroxyryptophan. 4-hydroxy piperidine or 4-piperidine carbinols are protected by Boc, introduce mesyl and obtain 4-first sulphurAcyl group-piperidines-1-carboxylic acid tertiary butyl ester or 4-mesyloxy methyl-piperidines-1-carboxylic acid tertiary butyl ester. Then potash,In DMF, obtain target compound with Deprotection under the condensation of replacement-5-hydroxyryptophan, acid condition.
In the compounds of this invention general formula (I), in the time of n=2, its preparation process is as follows:
This series compound is preparation technology comprise: 5-hydroxyryptophan is by being hydrolyzed under esterification, introducing acyl group, alkali conditionObtain replacing 5-hydroxyryptophan. 4-pyridylacetic acid hydrochloric acid ammonia, by high-pressure hydrogenation, Lithium Aluminium Hydride reduction, Boc protection, is introduced first sulphurAcyl group obtains 4-(2-mesyloxy ethyl)-piperidines-1-carboxylic acid tertiary butyl ester. Then at potash, N, N-dimethyl formylIn amine, obtain target compound with Deprotection under the condensation of replacement 5-hydroxyryptophan, acid condition.
The 5-hydroxyryptophan derivative that the compounds of this invention piperidyl replaces is by preliminary platelet aggregation-against experiment, knotFruit shows that this compounds has certain platelet aggregation inhibitory activity, can further develop as novel antithrombotic reagent.
Pharmacological experiment and the result of part of compounds of the present invention below:
Get rabbit carotid artery blood, be placed in the 15ml centrifuge tube (volume that every pipe is final of 3.8% sodium citrate that contains 1mlBe about 10ml), centrifugal 1000r/min, 18min, obtaining upper strata liquid is platelet rich plasma (PRP), remaining blood sample is with 3000r/The centrifugal 15min of min, obtains platelet poor plasma (PPP). Draw 300 microlitre PPP zeroings, then draw 270 microlitre PRP and be placed in advanceIn heat channel, what add variable concentrations is subject to test product 30 microlitres, and preheating is placed on test section in 3 minutes, adds derivant (ADP) 30 micro-Rise, measure platelet aggregation rate in 6min simultaneously. Wherein, blank is PBS buffer solution, and positive control is aspirin.
Experimental result is in table 1:
The experimental result of table 1 part of compounds platelet aggregation-against of the present invention
| Compound number | Inhibiting rate | Compound number | Inhibiting rate 6 --> |
| Aspirin | 24.48% | 6 | 15.68% |
| 1 | 13.69% | 7 | 27.11% |
| 2 | 10.73% | 8 | 32.95% |
| 3 | 25.37% | 9 | 35.85% |
| 4 | 13.26% | 10 | 39.72% |
| 5 | 12.88% | 11 | 52.90% |
Result shows all there is platelet aggregation inhibitory activity under the compounds of this invention 1mmol/L concentration. Wherein, compound 3,7,8,9,10 and 11 platelet aggregation-against ability is better than aspirin.
Detailed description of the invention
Embodiment 1
1,2-butyrylamino-3-[5-(piperidines-4-oxygen)-1H-indoles-3] the changing into of-propionic acid (compound 3)
1) synthetic 5-hydroxyryptophan methyl esters
In 500ml three-necked bottle, add 5-hydroxyryptophan 44.00g(0.20mol), methyl alcohol 350ml, be cooled to-5 DEG C. Low temperatureThe lower thionyl chloride 17.4ml (0.24mol) that slowly drips. After dropwising, rising to 25 DEG C of reactions spends the night. TLC detection (EA:MeOH:TEA=10:1:1) raw material disappears, and stops reaction. Methyl alcohol is fallen in decompression distillation, adds after cooling 30 DEG C, 300ml ethyl acetate to stir 2Hour, suction filtration, dries, and obtains pale solid 43.53g(92.90%). M.p.135～136 DEG C; Molecular formula: C12H14N2O3，HRMS(FAB)(m/z)：235.1060(M+H)+。
2) synthetic butyryl-5-hydroxyryptophan methyl esters
In 50ml three-necked bottle, add 5-hydroxyryptophan methyl esters 2.50g(0.01mol), pyridine 1.88g(0.02mol) acetonitrile20ml, keeps 30 DEG C to stir 1h. Slowly drip butyl chloride 1.25g(0.01mol). Drip and finish, rise to 56 DEG C of reactions and spend the night. TLC inspectionSurvey (PE:EA=1:1) raw material and disappear, stop reaction. Be evaporated to 5ml, add the dilution of 15ml water, after stirring, slowly dripAdd 6mol/L hydrochloric acid, be adjusted to acid 2-3, ethyl acetate extraction (20ml*3), combined ethyl acetate layer, washes with saturated common saltWash to neutrality anhydrous sodium sulfate drying. Suction filtration, removes solvent under reduced pressure and obtains brownish red solid 2.42g(77.5%), without refining, straightConnect and throw next step. Molecular formula: C16H20N2O4，HRMS(FAB)(m/z)：305.1421(M+H)+。
3) synthetic butyryl-5-hydroxyryptophan
In 50ml three-necked bottle, add butyryl-5-hydroxyryptophan methyl esters 1.00g(0.003mol), 5ml water, 5ml oxolane,5ml methyl alcohol, adds a hydronium(ion) oxidation lithium 0.35g(0.008mol after stirring and dissolving), after 25 DEG C of reaction 4h, TLC detects (PE:EA=1:1) raw material disappearance, stop reaction. Remove organic solvent under reduced pressure, slowly drip 1mol/L hydrochloric acid, adjustment of acidity is to 2-3, acetic acidEthyl ester extraction (10ml*3), combined ethyl acetate layer, saturated common salt is washed to neutrality, anhydrous sodium sulfate drying. Suction filtration, decompression is steamedDesolventize to obtain red solid 0.92g(96.1%), without refining, directly throw next step. Molecular formula: C15H18N2O4，HRMS(FAB)(m/z)：291.1331(M+H)+。
4) synthetic 4-hydroxy-piperdine-1-carboxylic acid tertiary butyl ester
In 150ml three-necked bottle, add 4-hydroxy piperidine 2.00g(0.02mol), triethylamine 3.6ml(0.03mol), dichloromethaneAlkane 50ml. Be cooled to 0 DEG C, slowly drip di-tert-butyl dicarbonate 3.79g(0.02mol). Drip and finish, 25 DEG C of reactions are spent the night, TLC inspectionSurvey (PE:EA=2:1) raw material and disappear, stop reaction. Remove carrene under reduced pressure, add 40ml ethyl acetate, saturated common salt washingTo neutral, anhydrous sodium sulfate drying. Suction filtration, removes solvent under reduced pressure and obtains white solid 3.89g(97.7%). M.p.61～65 DEG C; PointMinor: C10H19NO3，HRMS(FAB)(m/z)：201.2610(M+H)+。
5) synthetic 4-mesyl-piperidines-1-carboxylic acid tertiary butyl ester
In 50ml three-necked bottle, add 4-hydroxy-piperdine-1-carboxylic acid tertiary butyl ester 2.00g(0.01mol), triethylamine 2.9ml(0.02mol), carrene 20ml. Be cooled to 0 DEG C, slowly drip mesyl chloride 1.0ml(0.01mol). Drip and finish, continue to keep0 DEG C of reaction 2h, TLC detects (PE:EA=2:1) raw material and disappears, and stops reaction. Add 10ml water slowly to drip 1mol/L hydrochloric acid, adjustJoint is acid to 4, stratification, and organic layer is washed to neutrality, and anhydrous sodium sulfate drying filters, and removes solvent under reduced pressure and obtains white solidBody 2.65g(95.5%). M.p.88～89 DEG C; Molecular formula: C11H21NO5S，HRMS(FAB)(m/z)：279.3531(M+H)+，found279.3535。
6) synthetic 4-[3-(2-butyrylamino-2-carboxyl-ethyl-1H-indoles-5-oxygen]-piperidines-1-carboxylic acid tertiary butyl ester
In 50ml three-necked bottle, add butyryl-5-hydroxyryptophan 0.87g(0.003mol), 4-mesyl-piperidines-1-carboxylic acidTertiary butyl ester 1.54g(0.006mol), DMF20ml, be stirred to molten. Add Anhydrous potassium carbonate 1.14g(0.008mol), nitrogen is protectedProtect down 80 DEG C of reaction 10h. TLC detects (PE:EA=1:1) raw material and disappears, and stops reaction. Suction filtration, collects filtrate, removes under reduced pressure moltenAgent obtains crude product. Silica gel column chromatography (eluant, eluent: PE:EA=2:1) purifying obtains transparent grease 0.93g(67.0%). M.p.112～114℃；1H-NMR(300MHz,DMSO-d6):δ11.95(s,1H,indole-NH-),10.53(s,1H,-COOH),8.60(d,1H,J=7.32,-NH-CO-),7.12(d,1H,J=8.58,Ar-H),7.03(d,1H,J=2.04,indole-H),6.79(d,1H,J=1.93,Ar-H),6.59(dd,1H,J1=1.93,J2=8.58,Ar-H),4.51～4.53(m,1H,-CH2-CH-COOH),3.81～3.84(m,1H,-O-CH-),2.95～3.16(m,2H,-CH 2-CH-COOH),2.73(t,2H,J=3.87,-CH 2-N-CH2-),2.67(t,2H,J=3.87,-CH 2-N-CH2-),2.05(t,2H,J=5.58,-CO-CH2-),1.87～1.96(m,4H,-CH 2-CH-CH 2),1.39(s,9H,-C(CH3)3),1.16～1.21(m,2H,-CH 2-CH3),0.83(t,3H,J=5.13,-CH2-CH 3)ppm。
7) synthetic 2-bytyry amino-3-[5-(piperidin-4-yl Oxy-1 H-indol-3-yl]-propionic acid
In 50ml three-necked bottle, add 4-[3-(2-butyrylamino-2-carboxyl-ethyl-1H-indoles-5-oxygen]-piperidines-1-carboxylicAcid tertiary butyl ester 0.90g(0.002mol), carrene 18ml. Be cooled to-5 DEG C, slowly drip trifluoroacetic acid 8.0ml(0.12mol). After dropwising, rise to room temperature reaction 2h. TLC detects (PE:EA=1:1) raw material and disappears, and stops reaction. Decompression is steamedExcept carrene, slowly drip saturatedly, regulate sodium acid carbonate, adjustment of acidity is to 4-5, and ethyl acetate extraction (15ml*3), mergesOrganic layer, anhydrous sodium sulfate drying. Suction filtration, removes solvent under reduced pressure and obtains off-white color solid 0.60g(83.9%). M.p.103～104DEG C; Molecular formula: C20H27N3O4，HRMS(FAB)(m/z)：374.2067(M+H)+；1H-NMR(300MHz,DMSO-d6):δ10.55(s,1H,indole-NH-),9.04(s,1H,-COOH),8.22(d,1H,J=7.98,-NH-CO-),7.13(d，1H,J=8.76,Ar-H),7.11(d，1H,J=2.10,indole-H),7.03(d,1H,J=2.24,Ar-H),6.58(dd,1H,J1=2.25,J2=8.76,Ar-H),4.89～4.92(m,1H,-CH2-CH-COOH),3.58～3.60(m,1H,-O-CH-),3.18(d,2H,J=7.08,-CH 2-CH-COOH),2.71～3.04(m,4H,-CH 2-N-CH 2-),2.07(t,2H,J=5.58,-CO-CH2-),1.43～1.50(m,2H,-CH 2-CH3),1.14～1.27(m,4H,-CH 2-CH-CH 2-),0.91(t,3H,J=3.93,-CH2-CH 3)ppm。
Embodiment 2
1,2-acetylaminohydroxyphenylarsonic acid 3-[5-(piperidines-4-oxygen)-1H-indoles-3] synthetic (compound 1) of-propionic acid.
According to the preparation method of compound 3, replace butyl chloride with chloroacetic chloride, all the other operations are identical. Product is that off-white color is solidBody. Molecular formula: C18H23N3O4，HRMS(FAB)(m/z)：346.1727(M+H)+；
Embodiment 3
1,2-propionamido-3-[5-(piperidines-4-oxygen)-1H-indoles-3] synthetic (compound 2) of-propionic acid.
According to the preparation method of compound 3, replace butyl chloride with propionyl chloride, all the other operations are identical. Product is pale yellow colored solidBody. Molecular formula: C19H25N3O4，HRMS(FAB)(m/z)：360.1902(M+H)+；
Embodiment 4
1,2-benzamido-3-[5-(piperidines-4-oxygen)-1H-indoles-3] synthetic (compound 4) of-propionic acid.
According to the preparation method of compound 3, replace butyl chloride with chlorobenzoyl chloride, all the other operations are identical. Product is faint yellowSolid. Molecular formula: C23H25N3O4，HRMS(FAB)(m/z)：408.1924.1902(M+H)+；
Embodiment 5
1,2-methanesulfonamido-3-[5-(piperidines-4-oxygen)-1H-indoles-3] synthetic (compound 5) of-propionic acid.
According to the preparation method of compound 3, replace butyl chloride with mesyl chloride, all the other operations are identical. Product is faint yellowSolid. Molecular formula: C17H23N3O5S，HRMS(FAB)(m/z)：382.1422.1902(M+H)+；
Embodiment 6
1,2-fourth sulfonamido-3-[5-(piperidines-4-oxygen)-1H-indoles-3] synthetic (compound 6) of-propionic acid.
According to the preparation method of compound 3, replace butyl chloride with mesyl chloride, all the other operations are identical. Product is brown solidBody. Molecular formula: C20H29N3O5S，HRMS(FAB)(m/z)：424.1902(M+H)+；
Embodiment 7
1,2-butyrylamino-3-[5-(piperidines-4-methoxyl group)-1H-indoles-3] synthetic (compound 7) of-propionic acid.
According to the preparation method of compound 3, replace 4-hydroxy piperidine with 4-piperidine carbinols, all the other operations are identical. Product isOff-white color solid. Molecular formula: C21H29N3O4，HRMS(FAB)(m/z)：388.2235(M+H)+；
Embodiment 8
1,2-benzamido-3-[5-(piperidines-4-methoxyl group)-1H-indoles-3] synthetic (compound 8) of-propionic acid.
According to the preparation method of compound 7, replace butyl chloride with chlorobenzoyl chloride, all the other operations are identical. Product is faint yellowSolid. Molecular formula: C24H27N3O4，HRMS(FAB)(m/z)：422.2005(M+H)+；
Embodiment 9
3-[5-(piperidin-4-yl methoxyl group-1H-indol-3-yl]-2-[(pyridine-4-carbonyl)-amino]-propionic acid is synthetic(compound 9).
According to the preparation method of compound 7, with different nicotinoyl chlorine replacement butyl chloride, all the other operations are identical. Product is faint yellowSolid. Molecular formula: C23H24N4O4，HRMS(FAB)(m/z)：423.2035(M+H)+；
Embodiment 10
1,2-fourth sulfonamido-3-[5-(piperidines-4-methoxyl group)-1H-indoles-3] synthetic (compound 10) of-propionic acid.
According to the preparation method of compound 7, with fourth sulfonic acid chloride replacement butyl chloride, all the other operations are identical. Product is brown solidBody. Molecular formula: C21H31N3O5S，HRMS(FAB)(m/z)：438.2017(M+H)+；
Embodiment 11
2-(2-carboxyl acetyl-amino-3-[5-(piperidin-4-yl methoxyl group-1H-indol-3-yl] (change synthesizing of-propionic acidCompound 11).
1) synthetic N-[1-carboxyl-2-(5-hydroxyl-1H-indol-3-yl)-ethyl]-succinamic acid
In 50ml three-necked bottle, add successively 5-hydroxyryptophan 2.20g(0.01mol), succinic anhydride 1.00g(0.01mol),Glacial acetic acid 20ml. Rise to 60 DEG C and stir 15h, TLC(EA:MeOH=1:1) detect raw material disappearance, stop reaction. Remove under reduced pressure moltenAgent, the water-soluble solution of 10ml, ethyl acetate extraction (10ml*3), merges organic phase, anhydrous sodium sulfate drying. Suction filtration, removes under reduced pressure moltenAgent, obtains yellow solid 2.98g(93.12%) without refining, directly throw next step. Molecular formula: C15H16N2O6，HRMS(FAB)(m/z)：321.1023(M+H)+。
According to the preparation method of compound 7, all the other operations are identical. Product is faint yellow solid. Molecular formula: C21H27N3O6，HRMS(FAB)(m/z)：418.1917(M+H)+；
Embodiment 12
1,2-butyrylamino-3-[5-(piperidin-4-yl ethyoxyl)-1H-indoles-3] synthetic (compound 12) of-propionic acid
1) synthetic 4-Piperidineacetic acid
By 4-pyridine acetic acid hydrochloride 5.00g(0.03mol), Pd/C0.5g, water 50mL add in autoclave successively, pass intoH2, keeps 7MPa, and 95 DEG C are stirred 5h, filter, and remove water under reduced pressure and obtain white solid 4.95g(95.7%), without refining, directly throwNext step. Molecular formula: C7H13NO2，HRMS(FAB)(m/z)：144.1823(M+H)+。
2) synthetic 4-piperidines ethanol
By Lithium Aluminium Hydride 2.07g(0.06mol) in the protection of N2 gas, under the water-cooled condition of ice, add anhydrous tetrahydro furanIn 80mL, by the 4-Piperidineacetic acid 4.95g(0.03mol grinding) slowly add in reactant liquor, in this process, control reaction temperatureBe less than 30 DEG C. Rising to 25 DEG C of reactions spends the night. Be cooled to 0 DEG C, slowly drip successively water 3mL, 30% sodium hydrate aqueous solution 3mL, water3mL. Rise to 25 DEG C and stir 30min. Filter, remove solvent under reduced pressure and obtain faint yellow solid 2.23g(62.5%). M.p.46～47 DEG C;Molecular formula: C7H15NO，HRMS(FAB)(m/z)：130.2011(M+H)+。
3) synthetic 4-hydroxyethyl piperidine-1-carboxylic acid tertiary butyl ester
In 150ml three-necked bottle, add 4-piperidines ethanol 1.50g(0.01mol), triethylamine 2.4ml(0.02mol), dichloromethaneAlkane 30ml. Be cooled to 0 DEG C, slowly drip di-tert-butyl dicarbonate 2.54g(0.01mol). Drip and finish, 25 DEG C of reactions are spent the night, TLC inspectionSurvey (PE:EA=2:1) raw material and disappear, stop reaction. Remove carrene under reduced pressure, add 40ml ethyl acetate, saturated common salt washingTo neutral, anhydrous sodium sulfate drying. Suction filtration, removes solvent under reduced pressure and obtains transparent grease 2.27g(85.2%). Molecular formula:C12H23NO3，HRMS(FAB)(m/z)：229.3206(M+H)+。
4) synthetic 4-methylsulfonylethyl-piperidines-1-carboxylic acid tertiary butyl ester
In 150ml three-necked bottle, add 4-hydroxymethyl piperidine-1-carboxylic acid tertiary butyl ester 2.00g(0.01mol), triethylamine2.8ml(0.02mol), carrene 30ml. Be cooled to 0 DEG C, slowly drip mesyl chloride 0.9ml(0.01mol). Drip and finish, continue0 DEG C of reaction 2h is held in continuation of insurance, and TLC detects (PE:EA=2:1) raw material and disappears, and stops reaction. Add 20ml water slowly to drip 1mol/LHydrochloric acid, adjustment of acidity to 4, stratification, organic layer is washed to neutrality, anhydrous sodium sulfate drying. Suction filtration, removes solvent under reduced pressure and obtainsWhite solid 2.30g(80.5%). M.p.81～82 DEG C; Molecular formula: C13H25NO5S，HRMS(FAB)(m/z)：308.1547(M+H)+。
5) synthetic 4-[3-(2-butyrylamino-2-carboxyl-ethyl-1H-indoles-4-base oxethyl]-piperidines-1-carboxylic acid uncleButyl ester
In 50ml three-necked bottle, add butyryl-5-hydroxyryptophan 0.2g(0.0007mol), 4-methylsulfonylethyl-piperidines-1-Carboxylic acid tertiary butyl ester 0.28g(0.0009mol), DMF5ml, be stirred to molten. Add Anhydrous potassium carbonate 0.25g(0.0018mol),Under nitrogen protection, 80 DEG C of reaction 10h. TLC detects (PE:EA=1:1) raw material and disappears, and stops reaction. Suction filtration, collects filtrate, decompressionSteaming desolventizes to obtain crude product. Silica gel column chromatography (eluant, eluent: PE:EA=2:1) purifying obtains yellow oil 0.11g(31.8%).m.p.108～109℃；1H-NMR(300MHz,DMSO-d6):δ10.53(s,1H,indole-NH-),8.23(s,1H,-COOH),7.98(d,1H,J=7.56,-NH-CO-),7.12(d,1H,J=7.22,Ar-H),7.03(s,1H,Ar-H),6.79(s,1H,Ar-H),6.58(d,1H,J=7.22,Ar-H),4.41～4.47(m,1H,-CH2-CH-COOH),3.83(t,2H,J=5.88,-O-CH 2-),3.21～3.36(m,4H,-CH 2-N-CH 2-),2.94(d,2H,J=4.68,-CH 2-CH-COOH),2.82～2.91(m,2H,-O-CH2-CH 2-),2.06(t,2H,J=7.23,-CO-CH 2-),1.92～1.99(m,4H,-CH 2-CH-CH 2-),1.80～1.85(m,1H,-CH2-CH-CH2-),1.38(s,9H,-C(CH3)3),1.15～1.20(m,2H,-CH 2-CH3),0.82(t,3H,J=7.20,-CH2-CH 3)ppm。
6) synthetic 2-bytyry amino-3-[5-(piperidin-4-yl ethyoxyl-1H-indol-3-yl]-propionic acid
In 50ml three-necked bottle, add 4-[3-(2-butyrylamino-2-carboxyl-ethyl-1H-indoles-4-ylmethoxy]-piperazinePyridine-1-carboxylic acid tertiary butyl ester 0.11g(0.0002mol), carrene 5ml. Be cooled to-5 DEG C, slowly drip trifluoroacetic acid0.95ml(0.015mol). After dropwising, rise to room temperature reaction 2h. TLC detects (PE:EA=1:1) raw material and disappears, and stops anti-Should. Remove carrene under reduced pressure, slowly drip saturatedly, regulate sodium acid carbonate, adjustment of acidity is to 4-5, ethyl acetate extraction (5ml*3), merge organic layer, anhydrous sodium sulfate drying. Suction filtration, removes solvent under reduced pressure and obtains yellow solid 0.04g(83.3%). M.p.109～110 DEG C; Molecular formula: C22H31N3O5，HRMS(FAB)(m/z)：402.2392(M+H)+；1H-NMR(300MHz,DMSO-d6):δ10.54(s,1H,indole-NH-),8.63(s,1H,-COOH),8.18(d,1H,J=7.26,-NH-CO-),7.12(d,1H,J=8.55,Ar-H),7.03(s,1H,indole-H),6.79(s,1H,Ar-H),6.58(d,1H,J=8.55,Ar-H),4.43～4.45(m,1H,-CH2-CH-COOH),3.58(t,2H,J=7.11,-O-CH 2-),3.23～3.36(m,4H,-CH 2-N-CH 2-),3.00～3.06(m,2H,-CH 2-CH-COOH),2.87～2.94(m,2H,-O-CH2-CH 2-),2.06(t,2H,J=7.05,-CO-CH2-),1.80～1.85(m,1H,-CH2-CH-CH2-),1.49～1.63(m,2H,-CH 2-CH3),1.23～1.47(m,4H,-CH 2-CH-CH 2-),0.81(t,3H,J=6.96,-CH2-CH 3)ppm。
Embodiment 13
1,2-benzamido-3-[5-(piperidines-4-ethyoxyl)-1H-indoles-3] synthetic (compound 13) of-propionic acid.
According to the preparation method of compound 12, replace butyl chloride with chlorobenzoyl chloride, all the other operations are identical. Product is faint yellowSolid. Molecular formula: C25H29N3O4，HRMS(FAB)(m/z)：436.2005(M+H)+；
Embodiment 14
1,2-fourth sulfonamido-3-[5-(piperidines-4-ethyoxyl)-1H-indoles-3] synthetic (compound 14) of-propionic acid.
According to the preparation method of compound 12, with fourth sulfonic acid chloride replacement butyl chloride, all the other operations are identical. Product is brown solidBody. Molecular formula: C22H33N3O5S，HRMS(FAB)(m/z)：452.2017(M+H)+。
Claims (7)
1. the piperidyl of general formula (I) replaces 5-hydroxyryptophan derivative or its pharmaceutically acceptable salt:
Wherein R1Represent H, CH3Or CH2CH3；
R2RepresentWherein R3Represent the C replacing arbitrarily1-C10Alkyl, the arbitrarily phenyl that replaces or the benzyl replacing arbitrarilyBase; Wherein the substituting group of alkyl is hydrogen, halogen, hydroxyl, cyano group or amino; The substituting group of phenyl is halogen, nitro, amino, hydroxylBase or C1-C10Alkoxyl; The substituting group of benzyl is hydrogen, halogen, nitro, amino, hydroxyl or C1-C10Alkoxyl
R2Also representR5Represent C1-C10Alkyl;
n＝0～5。
2. the piperidyl of claim 1 replaces 5-hydroxyryptophan derivative or its pharmaceutically acceptable salt, wherein R2Represent fourthAcyl group, fourth sulfonyl or benzoyl.
3. the preparation method of the 5-hydroxyryptophan derivative that the piperidyl of claim 1 replaces, works as R1While representing H, comprising:
Wherein R2With the definition of n with claim 1.
4. a pharmaceutical composition, wherein contain claim 1 piperidyl replace 5-hydroxyryptophan derivative or its pharmacyUpper acceptable salt and pharmaceutically acceptable carrier.
5. the piperidyl of claim 1 replaces 5-hydroxyryptophan derivative or its pharmaceutically acceptable salt are little for the preparation of bloodThe purposes of plate sugar memebrane protein IIb/IIIa acceptor inhibitor.
6. the 5-hydroxyryptophan derivative that the piperidyl of claim 1 replaces or its pharmaceutically acceptable salt are for the preparation for the treatment ofThe purposes of the medicine of thrombotic diseases.
7. the 5-hydroxyryptophan derivative that the piperidyl of claim 1 replaces or its pharmaceutically acceptable salt are for the preparation of anti-bloodPlatelet is assembled the purposes of medicine.
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